(Chest. 2002;121:1818-1823.)
© 2002
American College of Chest Physicians
Pulmonary Function Characteristics in Patients With Different Patterns of Methacholine Airway Hyperresponsiveness*
Annie Lin Parker, MD, FCCP and
Dennis McCool, MD, FCCP
* From the Department of Pulmonary and Critical Care Medicine, Memorial Hospital of Rhode Island and Brown Medical School, Providence, RI.
Correspondence to: Annie L. Parker, MD, FCCP, Department of Pulmonary and Critical Care Medicine, Memorial Hospital of Rhode Island, 111 Brewster St, Pawtucket, RI 02860; e-mail: Annie_Parker{at}brown.edu
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Abstract
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Study objectives: The American Thoracic Society guidelines for methacholine-induced airway hyperresponsiveness include a 
20% reduction in FEV1 or a 40% reduction in specific airway conductance (sGaw). The objectives of the current study are to assess the concordance between these two criteria and to characterize the pulmonary function and respiratory symptoms of patients with different patterns of methacholine hyperresponsiveness.
Study design: A prospective study of 248 consecutive patients referred for methacholine bronchoprovocation testing.
Results: Positive methacholine hyperresponsiveness was noted in 179 patients; 139 patients (78%) had a 20% reduction in FEV1, whereas 40 patients (22%) had a 40% reduction in sGaw alone without a significant change in FEV1. The former group had the following: (1) higher baseline lung volumes, (2) lower baseline values of FEV1 and sGaw, (3) forced expiratory flow between 25% and 75% of vital capacity (FEF25–75)/FVC ratios compared to patients with a reduction in sGaw alone (0.72 ± 0.26 vs 0.97 ± 0.28, mean ± SD; p < 0.0001), and (4) more frequent presence of wheezing and chest tightness (p < 0.05).
Conclusions: First, a substantial number of patients have a reduction in SGaw alone in response to methacholine, and secondly, this response is seen in patients with a higher FEF25–75/FVC ratio. Since the FEF25–75/FVC ratio is thought to be an index of airway size relative to lung size, we speculate that the larger intrinsic airway size relative to lung size may explain the differences in baseline parameters and patterns of methacholine hyperresponsiveness.
Key Words: asthma • bronchial provocation test • dysanapsis • methacholine
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Introduction
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Methacholine bronchoprovocation testing is frequently used to diagnose airway hyperresponsiveness and asthma. Therefore, criteria used to interpret the bronchoprovocation test will have a major impact on the diagnosis and management of asthmatic patients. Indexes of expiratory airflow obstruction and other functional changes that may be elicited by methacholine are typically assessed. A 20% reduction in FEV1 following methacholine administration is a common parameter used to determine airway hyperresponsiveness. Alternatively, a 40% reduction in specific airway conductance (sGaw) can be used to determine airway hyperresponsiveness.1
2
Regardless of which test is selected, according to the American Thoracic Society guidelines, the changes in the test parameter following methacholine challenge must exceed 2 SDs or coefficients of variation for repeated measures in the same individual before a statistically significant change can be established.2
The change in FEV1 following methacholine challenge is the most widely applied criterion in the evaluation of airway hyperresponsiveness. It is easily performed and is highly reproducible. By contrast, the change in sGaw following methacholine challenge is less frequently used. A recent survey3
of 44 investigators who have published articles in which a bronchoprovocation technique was used revealed that 78% of them used FEV1 criterion alone to measure the response to bronchoprovocation and only 12% routinely measured SGaw. Similarly, we surveyed all the pulmonary function laboratories in the state of Rhode Island and found that of the > 2,000 bronchoprovocation tests that are performed annually, < 20% included an assessment of SGaw. The lack of equipment needed to measure SGaw or the unfamiliarity with methods used to measure airways resistance and conductance may account for the infrequent use of this test.2
Measurements of airways conductance or resistance may complement routine measures of expiratory airflow by providing further insights in the interpretation of bronchoprovocation tests. Large, central airway obstruction is best detected by SGaw measurements, while both large and small airway narrowing will affect measurements of FEV1.2
Since these two measurements detect obstruction in different locations of the airways, different patterns of reaction to methacholine challenge may indicate different types of airway hyperresponsiveness. Furthermore, although the American Thoracic Society guidelines consider a reduction in either the FEV1 or SGaw as adequate for the assessment of airway hyperresponsiveness, the degree of concordance between these two criteria is not well documented. The purposes of this study were to evaluate the concordance between the FEV1 and SGaw criteria in diagnosing airways hyperresponsiveness, and to determine differences in baseline pulmonary function characteristics and asthmatic symptoms in patients with different patterns of methacholine airway hyperresponsiveness.
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Materials and Methods
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Subjects
This was a prospective study of 248 consecutive patients, between May 1998 and October 1999, who were referred to our pulmonary function laboratory for methacholine bronchoprovocation testing and lung volume measurements for symptoms suggestive of asthma.
Pulmonary Function Testing
Spirometry was performed using standard techniques4
(Transfer Test Model C Dry Rolling Seal Spirometer; Morgan Scientific; Haverhill, MA). Forced expiratory maneuvers were performed in triplicate, and the best effort was analyzed. Following spirometry, lung volumes and SGaw were determined by variable-pressure body plethysmography (Warren E. Collins, Inc.; Braintree, MA). Body plethysmography measurements were obtained by taking the average of the best three maneuvers.5
All testing was performed with the patient in a seated position. The pulmonary function test data were expressed as a percentage of predicted normal values.6
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Methacholine Bronchoprovocation Protocol
Serial dilutions of methacholine chloride (Provocholine; Methapharm; Branford, ON, Canada) were prepared in normal saline solution containing 0.4% phenol (pH 7.0) and passed through bacterial-retentive filters with 0.2-µm porosity. Methacholine aerosol was delivered using a Rosenthal French Nebulization Dosimeter (Model 2A; Laboratory for Applied Immunology; Baltimore, MD) and a DeVilbiss Nebulizer (Model 646; DeVilbiss; Somerset, PA) set for a 0.6-s delivery time powered by a cylinder of compressed air with the regulator set at 20 pounds per square inch. Following a control inhalation of diluent, each patient took five slow inhalations from functional residual capacity (FRC) to total lung capacity (TLC) from the dosimeter starting at a concentration of 0.025 mg/mL. A FVC maneuver was performed within 5 min of methacholine inhalation. If the reduction in FEV1 was < 20% from baseline, five inhalations of increasing concentrations of methacholine, 0.25, 2.5, 10, and 25 mg/mL, were administered. The corresponding total cumulative units (CUs) were 0.125, 1.4, 14, 64, and 189 CU, with one dose unit being one inhalation of 1 mg/mL. The study was terminated and SGaw was obtained when FEV1 fell by 20% at any concentration or when the maximum dose of methacholine (189 CU) had been administered.1
Questionnaire Data
A questionnaire was administered to all patients at the time of the methacholine bronchoprovocation testing, inquiring about the following: (1) presence of asthma symptoms (wheezing, cough, shortness of breath, chest tightness, or other); (2) frequency of symptoms (all the time, sometimes, rare); (3) presence of hay fever or allergic rhinitis; (4) presence of gastroesophageal reflux; (5) asthma triggers (environmental allergens, irritants, change in weather, exposure to cold air, exercise, emotional stress, drug, food, or other); (6) family history of asthma; and (7) smoking status. The questionnaire was designed to simulate a physician interview of a potential asthma patient in an office setting. Patients answered and turned in the questionnaire voluntarily at the time of the testing. The questionnaire was approved by the Internal Review Board of the Committee for the Use of Human Subjects in Research, Memorial Hospital of Rhode Island.
Data Analysis
Subjects were classified into three groups based on methacholine airway hyperresponsiveness: (1) nonreactive (FEV1[-])/SGaw[-]), (2) reactive by FEV1 criterion (FEV1[+]), and (3) reactive by SGaw criterion alone (FEV1[-]/SGaw[+]). Group mean values for all baseline pulmonary function data were calculated and expressed as mean ± SD. Differences were determined among groups by using analysis of variance and the Fisher least-significant difference multiple-comparison test (StatView; SAS Institute; Cary, NC). Differences in symptoms and history between groups obtained by the questionnaire were assessed using 2 x 2 table and the Fisher exact test (StatView). Differences were considered significant for p < 0.05.
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Results
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A total of 248 patients were included in the study. Sixty-nine patients were nonresponsive to methacholine up to 189 CU. One hundred thirty-nine patients were responsive by FEV1 criterion ( 20% reduction in FEV1; FEV1[+] group), and 40 patients (22%) of the responsive patients were responsive by sGaw criterion alone ( 40% reduction in sGaw with < 20% reduction in FEV1; FEV1[-]/sGaw[+] group). On average, the FEV1(+) group had a 28.3 ± 8.9% reduction in FEV1 and a 48.4 ± 12.7% reduction in sGaw in response to 
189 CU of methacholine. There was a similar reduction in sGaw in the FEV1(-)/sGaw(+) group (49.9 ± 7.1%), but only an 11.1 ± 4.5% reduction in FEV1 in response to 189 CU of methacholine in this group. There were no differences in age, gender height, weight, or current smoking status among the three groups (Table 1
).
All lung volumes and baseline values of FEV1 were within the normal range for each group (Table 2
). However, there were significant differences in lung volumes and sGaw among groups. The patients who were positive by sGaw criterion alone (FEV1[-]/sGaw[+] group) had lower baseline lung volumes (TLC, FRC, and residual volume [RV]), and higher baseline indexes of forced expiratory flow (FEV1 and forced expiratory flow between 25% and 75% of vital capacity [FEF25–75]), sGaw, and FEF25–75/FVC ratios (0.97 ± 0.28 vs 0.72 ± 0.26, p < 0.0001) when compared to patients who had methacholine airway hyperresponsiveness by FEV1 criterion (FEV1[+] group; Table 2
). The FEF25–75/FVC ratio in the nonresponsive group was also significantly greater than that of FEV1(+) group (0.88 ± 0.27 vs 0.72 ± 0.26, p < 0.0001). When compared to the nonresponsive group, patients with positive responses by sGaw criterion alone (FEV1[-]/sGaw[(+)] group) had lower values of TLC and FRC and a greater baseline sGaw, but there were no differences in baseline FVC, FEF25–75, FEV1, or FEF25–75/FVC ratio between the two groups.
Since the FEV1(+) group had lower baseline FEV1 compared to the FEV1(-)/sGaw(+) group (91% of predicted vs 100% of predicted), one potential explanation for the difference in airway responsiveness patterns might be the presence of airflow limitation prior to the testing. To examine this possibility, a subgroup analysis was done on subjects with baseline FEV1 90% of predicted (n = 159). There were no difference in baseline percent- predicted FEV1 among the groups; however, the differences in FEF25–75/FVC ratios (0.81 ± 0.24 vs 1.00 ± 0.29, p = 0.0004), sGaw, TLC, FRC, and RV persisted between the FEV1(+) and FEV1(-)/sGaw(+) groups (Table 3
).
One hundred eighty-three patients returned the questionnaire (183 of 248 patients; 73.8%). The percentages of questionnaire returned were the same in all three groups (73.9% for the nonresponsive group, 73.4% for the FEV1(+) group, and 75.0% for FEV1(-)/sGaw[+] group). Results of the questionnaire for patients with methacholine airway hyperresponsiveness (FEV1[+] and FEV1[-]/sGaw[+] groups) are summarized in Tables 4
, 5
. The only significant differences in symptoms between these two groups of patients were the more frequent presence of wheezing (79.4% vs 46.7%, p = 0.009) and chest tightness (75.5% vs 53.3%, p = 0.02) in the FEV1(+) group. There were no differences in history of hay fever or allergic rhinitis, the presence of gastroesophageal reflux, asthma triggers, smoking status, and family history of asthma between the two groups.
When the questionnaire data were analyzed in the subgroup with 90% of predicted FEV1, the differences in frequency of wheezing (76.8% vs 43.5%, p = 0.003) and chest tightness (83.9% vs 47.8%, p = 0.001) persisted despite the lack of difference in baseline FEV1 between the FEV1(+) and FEV1(-)/SGaw groups.
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Discussion
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We found that 22% of patients with methacholine airway hyperresponsiveness had only a reduction in SGaw without a significant change in FEV1. This group of patients had smaller lung volumes (TLC, FRC, and RV), higher indexes of expiratory flow (FEV1 and FEF25–75), higher baseline values of SGaw, and higher baseline FEF25–75/FVC ratios than patients who had positive methacholine challenge results by FEV1 criterion. We will discuss how the two different patterns of airway hyperresponsiveness (FEV1[+] group vs FEV1[-]/SGaw[+] group) relate to differences in baseline measures of pulmonary function between the groups.
Green and colleagues8
proposed that inherent differences in airway size could account for the intersubject variability of maximal expiratory flow-volume curves. They suggested that there were substantial between-individual differences in airway size and function, independent of lung parenchymal size. These differences may have an embryologic basis reflecting physiologically normal but disproportionate growth of the airways and parenchyma within the lung. They termed this phenomenon dysanapsis and speculated that differences in the airway- parenchymal relationship might influence the pathogenesis of airway diseases. Mead9
subsequently showed that dysanapsis manifested itself by an inverse relationship between vital capacity (VC) and the product of the ratio of maximal flow at 50% of VC (Vmax50) divided by VC and the static recoil pressure of the lung at 50% of VC (Pst[L]50), Vmax50/VC x Pst[L]50. A low (Vmax50/VC x Pst[L]50)/VC ratio would indicate smaller airways relative to the lung parenchyma. Tager and colleagues10
later demonstrated that the ratio of FEF25–75 to the FVC could be used as a surrogate measure of dysanapsis.8
9
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A major advantage of using the FEF25–75/FVC ratio is that both parameters can be derived from a maximal expiratory flow-volume loop.
Individuals with small airways relative to lung size may be more likely to have expiratory flow limitation develop than individuals without dysanapsis. In support of this assertion, Litonjua et al11
found that the FEF25–75/FVC ratio was negatively associated with the degree of methacholine airway responsiveness (as assessed by the slope of the log10 dose and FEV1 relationship) in a group of 929 middle-aged and older men. Our data are also consistent with this observation. The FEF25–75/FVC ratio was lower in patients with methacholine hyperresponsiveness, as assessed by FEV1 criterion, than in nonresponsive patients. However, the FEF25–75/FVC ratio was not different in patients with methacholine airway hyperresponsiveness manifested by a reduction in SGaw alone when compared to nonresponders.
Differences in airways size relative to lung volume may be one of the mechanisms accounting for the two different patterns of airway hyperresponsiveness that we describe. The pattern characterized by a reduction in SGaw without a significant change in FEV1 suggests that methacholine induces narrowing of airways in a location downstream from the equal pressure point, such as the extrathoracic airway. Airway cross-sectional area is one of the key determinants of the location of the equal pressure point. Since the FEF25–75/FVC ratio was significantly greater in the FEV1(-)/SGaw(+) group, these individuals may have larger airways and are less likely to decrease their FEV1 for a given degree of bronchoconstriction than individuals with smaller airways. Although difference in the baseline FEF25–75/FVC ratio between the two groups support this mechanism, anatomic correlation would be necessary for confirmation. Since the phenomenon of dysanapsis between airway and parenchyma should present as a graded continuum in the general population and SGaw is a more sensitive indicator of airway narrowing, the possibility that individuals with SGaw reduction alone in response to methacholine may have a milder form of airway hyperresponsiveness that may later become more pronounced to involve reductions of both SGaw and FEV1 should also be considered.
Although the baseline FEV1 were within normal limits in all three groups, the FEV1(+) group had lower baseline FEV1 compared to FEV1(-)/SGaw(+) group (91% vs 100% of predicted). With 91% of predicted FEV1, it was unlikely that these subjects had severe airway obstruction at baseline. However, to exclude the possibility that underlying airflow limitation might be the reason for different patterns of airway hyperresponsiveness to methacholine, a subgroup analysis was done on subjects with 90% of predicted FEV1 at baseline. Significant difference in FEF25–75/FVC ratios persisted between groups with different patterns of airway hyperresponsiveness despite lack of difference in baseline FEV1. This result indicated that the different patterns could not be attributed to difference in baseline FEV1 or possible underlying airflow limitation. Dysanapsis, however, as indicated by the significantly different FEF25–75/FVC ratios, remained a possible mechanism. Other mechanisms that may account for the different pattern of airway hyperresponsiveness include: (1) regional differences in airway reactivity, ie, more reactive extrathoracic than intrathoracic airways; (2) differences in airway compliance, ie, lower unit change in cross-sectional area per unit change in pressure in the intrathoracic airways; and (3) differences in airway smooth-muscle mass.
Differences in airway sizes relative to the lung volume also may account for differences in baseline lung volumes and SGaw between the two groups. Larger airways would delay airway closure as one exhales to RV and therefore lower RV. Since airways resistance is an exponential function of airways size, airways resistance also would be reduced and its reciprocal (airways conductance) increased in individuals with larger airways. Our findings that baseline measures of RV were decreased and SGaw increased in the group with the higher FEF25–75/FVC ratio are consistent with the above-mentioned assertions.
Investigators8
9
who first coined the term dysanapsis had speculated that the airway-parenchyma relationship might influence the pathogenesis of airway diseases. The presence of smaller airways in infancy and early childhood appear to be a risk factor for developing childhood wheezing.12
13
By contrast, individuals with larger airways relative to lung size may be provided some protection from intrathoracic airway obstruction. All of the patients in the current study were referred for methacholine bronchoprovocation because of symptoms suggestive of asthma. There were no differences in the reported asthma triggers, presence of hay fever, allergic rhinitis, or gastroesophageal reflux or family history of asthma between the two groups. Therefore, it appeared that history alone could not predict the pattern of methacholine airway hyperresponsiveness. Both groups reported similar frequency of cough and shortness of breath, but the FEV1(+) group had more wheezing and chest tightness. The difference in frequency of wheezing and chest tightness also persisted when only subjects with 90% of predicted FEV1 were included to eliminated the possibility that baseline airflow limitation was the reason for difference in symptoms. The difference in symptomatology again could be consistent with different sites of obstruction, ie, predominantly intrathoracic airway obstruction in FEV1(+) group but not in the FEV1(-)/SGaw(+) group. Additional studies to further elucidate the mechanism of different patterns of airway hyperresponsiveness might provide insight to the pathogenesis of asthma.
The use of SGaw as a criterion for airway hyperresponsiveness had been challenged because a significant reduction in SGaw can be induced by bronchoprovocative agents, such as methacholine, in patients without a history or symptoms of asthma.14
15
16
However, data on changes in sGaw induced by methacholine in the nonasthmatic population were inadequate to support or refute this criticism. Airway hyperresponsiveness may occur in patients in the absence of clinical asthma. Patients with a > 40% reduction in SGaw in response to methacholine challenge have a form of methacholine airway hyperresponsiveness even though they may not have symptoms of asthma. Our data suggested that patients with a reduction in SGaw but not in FEV1 had less intrathoracic airway narrowing.
We conclude that a significant number of patients referred for evaluation of asthma may have negative methacholine challenge findings if only spirometry is performed and the SGaw response to methacholine is not measured. The observation that patients who had higher FEF25–75/FVC ratio react to methacholine by lowering SGaw without a reduction in FEV1 raises the possibility that airway-parenchyma relationships may play a role in the pathogenesis and/or location of airway obstruction. Further validation of this ratio as an indicator of airway-parenchyma dysanapsis could be useful in assessing an individual’s risk for airway diseases.
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Acknowledgements
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The authors are grateful for the technical support provided by Gail Dusseault and Laureen Sheehan.
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Footnotes
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Abbreviations: CU = cumulative unit; FEF25–75 = forced expiratory flow between 25% and 75% of vital capacity; FRC = functional residual capacity; Pst[L]50 = static recoil pressure of the lung at 50% of vital capacity; RV = residual volume; sGaw = specific airway conductance; TLC = total lung capacity; VC = vital capacity; Vmax50 = maximal flow at 50% of vital capacity
Received for publication June 8, 2001.
Accepted for publication December 19, 2001.
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References
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Abstract
Introduction
